rs6494227

Variant names:

• chr15-60813919-A-C
• rs6494227
• NM_134261.3:c.167-135233T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_134261.3(RORA):​c.167-135233T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0723 in 152,190 control chromosomes in the GnomAD database, including 544 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.072 (544 hom., cov: 32)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.579
• Publications: 4 publications found

Genes affected

RORA (HGNC:10258): (RAR related orphan receptor A) The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The encoded protein has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, as well as with NM23-1, the product of a tumor metastasis suppressor candidate gene. Also, it has been shown to aid in the transcriptional regulation of some genes involved in circadian rhythm. Four transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2014]

RORA Gene-Disease associations (from GenCC):

• intellectual developmental disorder with or without epilepsy or cerebellar ataxia

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3	c.167-135233T>G		intron_variant	Intron 1 of 10	ENST00000335670.11	NP_599023.1
RORA	XM_047432928.1	c.-1751-135233T>G		intron_variant	Intron 1 of 10		XP_047288884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORA	ENST00000335670.11	c.167-135233T>G		intron_variant	Intron 1 of 10	1	NM_134261.3	ENSP00000335087.6

Frequencies

GnomAD3 genomes AF: 0.0723 AC: 10991 AN: 152072 Hom.: 539 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0672

Gnomad FIN AF: 0.0901

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0559

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0723 AC: 11002 AN: 152190 Hom.: 544 Cov.: 32 AF XY: 0.0748 AC XY: 5567 AN XY: 74400

African (AFR) AF: 0.103 AC: 4283 AN: 41502

American (AMR) AF: 0.127 AC: 1939 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3470

East Asian (EAS) AF: 0.114 AC: 589 AN: 5180

South Asian (SAS) AF: 0.0670 AC: 323 AN: 4818

European-Finnish (FIN) AF: 0.0901 AC: 956 AN: 10612

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0394 AC: 2677 AN: 68012

Other (OTH) AF: 0.0549 AC: 116 AN: 2114

Alfa AF: 0.0650 Hom.: 58

Bravo AF: 0.0788

Asia WGS AF: 0.100 AC: 346 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.1
DANN	Benign	0.62
PhyloP100		0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6494227; hg19: chr15-61106118;